The present invention relates to an enhanced-circulation effector composition and method for treating a subject with small effector molecules which are normally subject to rapid renal clearance from the bloodstream.
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A number of emerging or current therapies involve intravenous injection of small (less than 50 Kdaltons) protein, polypeptide or polysaccharide effectors. Such effectors can include Fab antibody fragments, for use in active immunity; cytokines and cellular growth factors, for stimulating immunological inflammatory responses; hormones; and polysaccharides, which are capable of interacting with endothelial cell receptors to competitively block neutrophil binding to activated endothelial cells lining the blood vessel (Katre, Philips, Waldmann).
Other small polypeptide effectors have been proposed for use in blocking viral infection of target cells in the blood, such as a CD4+ glycopeptide which is effective to inhibit binding of human immunodeficiency virus (HIV) to CD4+ cells (Capon, Janeway).
Polymyxin B, a small basic peptide which is rapidly excreted by the kidneys, is known to react with and neutralize gram-negative bacterial endotoxins, specifically E. coli 0111:B4 liposaccharide (LPS) (Baldwin). It is not often administered parenterally as a treatment for septic shock syndrome, because high doses of polymyxin B are required for effective treatment. High doses can be fatal, due to renal toxicity, making advanced stages of septic shock difficult to treat.
The problem of rapid renal clearance observed with polymyxin B is also applicable to other small peptides, such as those discussed above, which have been used for parenteral treatment of disease. In general, circulating proteins which are smaller than about 50-60 Kdaltons will be cleared by the kidneys with a lifetime less than 1-2 hours.
In some cases, peptide molecular weight can be increased above the threshold 50-60 Kdalton size by derivatizing the peptide with biologically compatible polymers, such as polyethyleneglycol (PEG) (e.g., U.S. Pat. No. 4,179,337). However, this strategy may not always be effective for small effectors, e.g., those with molecular weights less than about 5-10 Kdalton. Moreover, derivatizing a polypeptide with a plurality of PEG chains may destroy or reduce the polypeptide activity, and/or mask key activity sites of the polypeptide.
The invention includes, in one aspect, a method of treating a subject by parenteral administration of a polypeptide or polysaccharide effector which is rapidly removed from the bloodstream by renal clearance in free form. The method includes parenterally administering to the subject, a liposome composition containing liposomes having an outer layer of polymer chains and the effector covalently attached to the distal ends of said chains. A preferred polymer is polyethylene glycol with chain lengths between about 1,000 and 10,000 daltons molecular weight.
Preferred effectors include:
(a) an antibody Fab fragment specific against a blood-circulating pathogen, for use in treating the subject for infection by the pathogen;
(b) a CD4 glycoprotein, for use in treating the subject for infection by human immunodeficiency virus (HIV);
(c) a cytokine or cellular growth factor, for use in stimulating an immune response in the subject;
(d) a mono or polysaccharide, such as sialyl Lewisx, which binds to endothelial leukocyte adhesion molecule (ELAM), for use in treating a vascular inflammation related to neutrophil recruitment into sites of inflammation;
(e) IL-1 inhibitor or IL-1RA, for treating the subject to achieve immune-response suppression;
(f) polymyxin B, or polymyxin B decapeptide, for treating the subject for septic shock; and
(g) a peptide hormone, for treating diseases subject to peptide hormone control.
In one specific embodiment, the invention includes a method of preventing progression of gram-negative bacteremia to septic shock and a method of treating acute septic shock by administering to a subject, a liposome composition containing liposomes having an outer layer of polyethylene glycol (PEG) chains and polymyxin B attached to the distal ends of the polymer chains.
In another aspect, the invention includes a composition of liposomes, each having an outer layer of polymer chains, typically polyethylene glycol chains, and one of the above effectors (a)-(g) attached to the distal ends of the chains.